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Study Designs for CLL/SLL Trials

Phase 3 trials studied the efficacy and safety of IMBRUVICA® as monotherapy or combination therapy in both frontline and relapsed/refractory CLL/SLL patients1

RESONATE™-2: IMBRUVICA® monotherapy vs. chlorambucil across several patient types1

IMBRUVICA® (ibrutinib) against ofatumumab—an approved agent for use in patients with previously treated Chronic lymphocytic leukemia (CLL) 

*Patients with IRC-confirmed progressive disease enrolled in an extension study for follow-up and second-line treatment per investigator’s choice (including ibrutinib for patients progressing on chlorambucil per the International Workshop on CLL criteria).2

  • PFS and ORR (CR and PR) were assessed by an IRC per iwCLL criteria2-4

RESONATE™-2 included patients with select high-risk characteristics1,2

IMBRUVICA® (ibrutinib) patient characteristics 

CLL=chronic lymphocytic leukemia, CR=complete response, del=deletion, ECOG=Eastern Cooperative Oncology Group, IGHV=immunoglobulin heavy-chain variable region gene, IRC=Independent Review Committee, iwCLL=International Workshop on CLL, ORR=overall response rate, OS=overall survival, PFS=progression-free survival, PR=partial response, PS=performance status, SLL=small lymphocytic lymphoma.

iLLUMINATE™: IMBRUVICA® + obinutuzumab vs chlorambucil + obinutuzumab across several patient types1

IMBRUVICA® (ibrutinib) against ofatumumab—an approved agent for use in patients with previously treated Chronic lymphocytic leukemia (CLL)

*In both arms, patients received 1000 mg of obinutuzumab on Days 1, 8, and 15 of the first cycle, followed by treatment on the first day of 5 subsequent cycles (total of 6 cycles, 28 days each). The first dose of obinutuzumab was divided between Day 1 (100 mg) and Day 2 (900 mg).1

†Chlorambucil was administered at a dose of 0.5 mg/kg on Days 1 and 15 of each 28-day cycle for 6 cycles.1

  • PFS and ORR (CR and PR) were assessed by an IRC per iwCLL criteria3-5

iLLUMINATE™ included patients with select high-risk characteristics1,5

pat_characteristics_illuminate 
  • At baseline, 65% of patients presented with CLL/SLL with high-risk factors (unmutated IGHV, del 17p/TP53 mutation, or del 11q)1

CLL=chronic lymphocytic leukemia, CR=complete response, del=deletion, ECOG=Eastern Cooperative Oncology Group, IGHV=immunoglobulin heavy-chain variable, IRC=Independent Review Committee, iwCLL=International Workshop on CLL, ORR=overall response rate, PFS=progression-free survival, PR=partial response, PS=performance status, SLL=small lymphocytic lymphoma.

RESONATE™: IMBRUVICA® vs ofatumumab across several patient types, including those with 17p deletion1

IMBRUVICA® (ibrutinib) randomized multicenter double-blind placebo-controlled phase 3 HELIOS trial 

PFS and ORR were assessed by an IRC per iwCLL criteria.1,3-4,7

  • The IRC evaluation of response per iwCLL criteria required CT scans for initial documentation of response as well as for confirmation of response7

RESONATE™ included patients with select high-risk characteristics1,7

IMBRUVICA® (ibrutinib) patient characteristics

CLL=chronic lymphocytic leukemia, CT=computed tomography, del=deletion, ECOG=Eastern Cooperative Oncology Group, IRC=Independent Review Committee, iwCLL=International Workshop on CLL, ORR=overall response rate, OS=overall survival, PFS=progression-free survival, PS=performance status, SLL=small lymphocytic lymphoma.

HELIOS: IMBRUVICA® + BR across several patient types

IMBRUVICA® (ibrutinib) randomized multicenter double-blind placebo-controlled phase 3 HELIOS trial

*In both arms, patients received BR for a maximum of six 28-day cycles. Bendamustine was dosed at 70 mg/m2 infused IV over 30 minutes on Cycle 1, Days 2 and 3, and thereafter on Cycles 2-6, Days 1 and 2. Rituximab was dosed at 375 mg/m2 on Cycle 1, Day 1, and thereafter at 500 mg/m2 on Cycles 2-6, Day 1.

PFS and ORR were assessed by an IRC per iwCLL criteria.3-4,8

  • CT scans were done at baseline and then every 12 weeks and were centrally reviewed and assessed by the IRC8

HELIOS included patients with select high-risk characteristics1,8

IMBRUVICA® (ibrutinib) patient characteristics 

BR=bendamustine and rituximab, CLL=chronic lymphocytic leukemia, CT=computed tomography, del=deletion, ECOG=Eastern Cooperative Oncology Group, IGHV=immunoglobulin heavy-chain variable, IRC=Independent Review Committee, IV=intravenous, iwCLL=International Workshop on CLL, ORR=overall response rate, OS=overall survival, PFS=progression-free survival, PS=performance status, SLL=small lymphocytic lymphoma.

 
 
 

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IMBRUVICA® (ibrutinib) is now approved in a new
formulation as one pill, once daily.

As of May 15, 2018, the original 140 mg capsules will no longer be available.
Every IMBRUVICA® patient will need a new prescription for the new pill.

Learn More
05/18 PRC-04135
References: 1. IMBRUVICA® (ibrutinib) Prescribing Information. Pharmacyclics LLC. 2019. 2. Burger JA, Tedeschi A, Barr PM, et al; for the RESONATE-2 Investigators. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373(25):2425-2437. 3. Hallek M, Cheson BD, Catovsky D, et al; International Workshop on Chronic Lymphocytic Leukemia. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute—Working Group 1996 guidelines. Blood. 2008;111(12):5446-5456. 4. Hallek M, Cheson BD, Catovsky D, et al. Response assessment in chronic lymphocytic leukemia treated with novel agents causing an increase of peripheral blood lymphocytes (e-Letter). Blood. 2012;119(23):5348. 5. Moreno C, Griel R, Demirkan F, et al. Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in first-line treatment of chronic lymphocytic leukaemia: primary results from the randomised phase 3 iLLUMINATE study. Lancet Oncol. 2019;20(1):43-56. 6. Data on file. Pharmacyclics LLC. 7. Byrd JC, Brown JR, O’Brien S, et al; for the RESONATE Investigators. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371(3):213-223. 8. Chanan-Khan A, Cramer P, Demirkan F, et al; for the HELIOS Investigators. Ibrutinib combined with bendamustine and rituximab compared with placebo, bendamustine, and rituximab for previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma (HELIOS): a randomised, double-blind, phase 3 study. Lancet Oncol. 2016;17(2):200-211.
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IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hemorrhage: Fatal bleeding events have occurred in patients treated with IMBRUVICA®. Grade 3 or higher bleeding events (intracranial hemorrhage [including subdural hematoma], gastrointestinal bleeding, hematuria, and post procedural hemorrhage) have occurred in 3% of patients, with fatalities occurring in 0.3% of 1,124 patients exposed to IMBRUVICA® in clinical trials. Bleeding events of any grade, including bruising and petechiae, occurred in 44% of patients treated with IMBRUVICA®.

The mechanism for the bleeding events is not well understood.

IMBRUVICA® may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies and patients should be monitored for signs of bleeding.

Consider the benefit-risk of withholding IMBRUVICA® for at least 3 to 7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.

Infections: Fatal and non-fatal infections (including bacterial, viral, or fungal) have occurred with IMBRUVICA® therapy. Grade 3 or greater infections occurred in 24% of 1,124 patients exposed to IMBRUVICA® in clinical trials. Cases of progressive multifocal leukoencephalopathy (PML) and Pneumocystis jirovecii pneumonia (PJP) have occurred in patients treated with IMBRUVICA®. Consider prophylaxis according to standard of care in patients who are at increased risk for opportunistic infections.

Monitor and evaluate patients for fever and infections and treat appropriately.

Cytopenias: Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (23%), thrombocytopenia (8%), and anemia (3%) based on laboratory measurements occurred in patients with B-cell malignancies treated with single agent IMBRUVICA®.

Monitor complete blood counts monthly.

Cardiac Arrhythmias: Fatal and serious cardiac arrhythmias have occurred with IMBRUVICA® therapy. Grade 3 or greater ventricular tachyarrhythmias occurred in 0.2% of patients, and Grade 3 or greater atrial fibrillation and atrial flutter occurred in 4% of 1,124 patients exposed to IMBRUVICA® in clinical trials. These events have occurred particularly in patients with cardiac risk factors, hypertension, acute infections, and a previous history of cardiac arrhythmias.

Periodically monitor patients clinically for cardiac arrhythmias. Obtain an ECG for patients who develop arrhythmic symptoms (e.g., palpitations, lightheadedness, syncope, chest pain) or new onset dyspnea. Manage cardiac arrhythmias appropriately, and if it persists, consider the risks and benefits of IMBRUVICA® treatment and follow dose modification guidelines.

Hypertension: Hypertension of any grade occurred in 12% of 1,124 patients treated with IMBRUVICA® in clinical trials. Grade 3 or greater hypertension occurred in 5% of patients with a median time to onset of 5.9 months (range, 0.03 to 24 months).

Monitor blood pressure in patients treated with IMBRUVICA® and initiate or adjust anti-hypertensive medication throughout treatment with IMBRUVICA® as appropriate.

Second Primary Malignancies: Other malignancies (10%) including non-skin carcinomas (4%) have occurred in 1,124 patients treated with IMBRUVICA® in clinical trials. The most frequent second primary malignancy was non-melanoma skin cancer (6%).

Tumor Lysis Syndrome: Tumor lysis syndrome has been infrequently reported with IMBRUVICA® therapy. Assess the baseline risk (e.g., high tumor burden) and take appropriate precautions.

Monitor patients closely and treat as appropriate.

Embryo-Fetal Toxicity: Based on findings in animals, IMBRUVICA® can cause fetal harm when administered to a pregnant woman. Advise women to avoid becoming pregnant while taking IMBRUVICA® and for 1 month after cessation of therapy. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Advise men to avoid fathering a child during the same time period.

ADVERSE REACTIONS

B-cell malignancies: The most common adverse reactions (≥20%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were thrombocytopenia (58%)*, diarrhea (41%), anemia (38%)*, neutropenia (35%)*, musculoskeletal pain (32%), rash (32%), bruising (31%), nausea (26%), fatigue (26%), hemorrhage (24%), and pyrexia (20%).

The most common Grade 3 or 4 adverse reactions (≥5%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were neutropenia (18%)*, thrombocytopenia (16%)*, and pneumonia (14%).

Approximately 7% (CLL/SLL), 14% (MCL), 14% (WM) and 10% (MZL) of patients had a dose reduction due to adverse reactions. Approximately 4-10% (CLL/SLL), 9% (MCL), and 7% (WM [5%] and MZL [13%]) of patients discontinued due to adverse reactions.

cGVHD: The most common adverse reactions (≥20%) in patients with cGVHD were fatigue (57%), bruising (40%), diarrhea (36%), thrombocytopenia (33%)*, muscle spasms (29%), stomatitis (29%), nausea (26%), hemorrhage (26%), anemia (24%)*, and pneumonia (21%).

The most common Grade 3 or higher adverse reactions (≥5%) reported in patients with cGVHD were pneumonia (14%), fatigue (12%), diarrhea (10%), neutropenia (10%)*, sepsis (10%), hypokalemia (7%), headache (5%), musculoskeletal pain (5%), and pyrexia (5%).

Twenty-four percent of patients receiving IMBRUVICA® in the cGVHD trial discontinued treatment due to adverse reactions. Adverse reactions leading to dose reduction occurred in 26% of patients.

*Treatment-emergent decreases (all grades) were based on laboratory measurements.

DRUG INTERACTIONS

CYP3A Inhibitors: Modify IMBRUVICA® dose as described in USPI sections 2.4 and 7.1.

CYP3A Inducers: Avoid coadministration with strong CYP3A inducers.

SPECIFIC POPULATIONS

Hepatic Impairment (based on Child-Pugh criteria): Avoid use of IMBRUVICA® in patients with severe baseline hepatic impairment. In patients with mild or moderate impairment, reduce IMBRUVICA® dose.

Please see full Prescribing Information.

Indications

IMBRUVICA® (ibrutinib) is a kinase inhibitor indicated for the treatment of adult patients with:

  • Mantle cell lymphoma (MCL) who have received at least one prior therapy.

    • Accelerated approval was granted for this indication based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

  • Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL).

  • CLL/SLL with 17p deletion.

  • Waldenström's macroglobulinemia (WM).

  • Marginal zone lymphoma (MZL) who require systemic therapy and have received at least one prior anti-CD20-based therapy.

    • Accelerated approval was granted for this indication based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

  • Chronic graft versus host disease (cGVHD) after failure of one or more lines of systemic therapy.


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IMBRUVICA® (ibrutinib) is covered by U.S. Patents, which are listed in FDA's Orange Book (available at https://www.accessdata.fda.gov/scripts/cder/ob/default.cfm).

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07/19 PRC-05238